Melanoma is one of the most aggressive cancers, often displaying resistance to targeted therapies, particularly those involving BRAF/MEK inhibitors. While these therapies offer significant benefits in certain melanoma subtypes, acquired resistance remains a critical challenge. Ferroptosis, an iron-dependent form of cell death, has recently emerged as a promising strategy to counteract this resistance. This study aims to explore the role of ferroptosis in melanoma and evaluate its potential as a therapeutic strategy in combination with BRAF/MEK inhibitors.

Human melanoma cell lines (A375, SK-MEL-28) with BRAF mutations were used to model melanoma resistance. Ferroptosis induction was assessed using specific inhibitors and activators of this pathway, such as RSL3 and erastin. Cell viability assays, gene expression analysis, and western blotting were performed to measure the effects of ferroptosis induction alone and in combination with BRAF/MEK inhibitors (e.g., vemurafenib and trametinib). Additionally, the response of melanoma cells to this combination treatment was evaluated through oxidative stress and cell death markers.

Our results show that induction of ferroptosis in melanoma cells significantly reduced cell viability and enhanced cell death, particularly when combined with BRAF/MEK inhibitors. Ferroptosis induction elevated oxidative stress levels, which appeared to sensitize melanoma cells to the effects of BRAF/MEK inhibitors. The combination treatment resulted in a synergistic therapeutic response, overcoming the resistance commonly seen with BRAF/MEK monotherapy. Gene expression analysis revealed upregulation of pro-ferroptotic and stress-response genes, supporting the potential of ferroptosis in combination therapy.

The induction of ferroptosis presents a promising strategy for enhancing the efficacy of BRAF/MEK inhibitors in the treatment of melanoma. Our findings suggest that ferroptosis could overcome treatment resistance and improve therapeutic outcomes in patients with advanced melanoma. Further preclinical and clinical studies are warranted to validate these results and optimize combination strategies involving ferroptosis and targeted inhibitors.